The goal of this program project is elucidate the mechanisms of angiogenic regulation by bringing together a unique collection of experienced investigators to integrate their multiple approaches, systems and modes of analysis. Outlined in this application are six projects designed to identify the biological signals that guide capillary growth and to analyze their mechanisms of action. These projects will use biochemical, molecular, morphological, cellular, immunocytochemical, and pharmacological methods of investigation both in vivo and in vitro. Project I will apply molecular biological methods to analyze the regulation of basic and acidic FGF (heparin-binding growth factor) gene expression. Project II will analyze the process by which capillary endothelial cell growth is controlled locally by extracellular matrix with special emphasis on mechanisms of signal transduction. Project III will use in vitro and in vivo methods to characterize the mechanisms and developmental role of EC-pericyte interactions in microvascular growth control. Project IV will investigate the molecular and cellular relationships amongst tumor cells, mast cells and endothelial cells in tumor angiogenesis. Project V will elucidate mechanisms of angiogenic regulation by determining the role played in the normal vascularization of avascular cartilage by mast cells, pericytes and angiogenic factors. Project VI will examine the mechanisms, biological effects, and therapeutic potential of angiogenesis inhibitors in vitro and in vivo. Through this approach we plan to define the principles of angiogenic regulation at the molecular, cellular and tissue levels.